The present invention relates to the field of L-nucleosides.
The last few decades have seen significant efforts expended in exploring possible uses of D-nucleoside analogs as antiviral agents. Some of this work has borne fruit, and a number of nucleoside analogs are currently being marketed as antiviral drugs, including the HIV reverse transcriptase inhibitors (AZT, ddI, ddC, d4T, and 3TC).
A variety of purine D-nucleoside analogs have also been explored in search of immuno-modulators. Guanosine analogs having substituents at the 7- and/or 8-positions, for example, have been shown to stimulate the immune system (for a review, see: Weigle, W. O. CRC Crit. Rev. Immunol. 1987, 7, 285; Lin et al. J. Med. Chem. 1985, 28, 1194-1198; Reitz, et al. J Med. Chem. 1994, 37, 3561-3578, Michael et al. J Med. Chem. 1993, 36, 3431-3436). Certain 3-∃-D-ribofuranosylthiazolo[4,5-d]pyrimidines have also demonstrated significant immunoactivity, including murine spleen cell proliferation and in vivo activity against Semliki Forest virus (Nagahara, et al. J. Med. Chem. 1990, 33, 407-415; Robins et al. U.S. Pat. No. 5,041,426). In other research, 7-Deazaguanosine and analogs have been shown to exhibit antiviral activity in mice against a variety of RNA viruses, even though the compound lacks antiviral properties in cell culture. 3-Deazaguanine nucleosides and nucleotides have also demonstrated significant broad spectrum antiviral activity against certain DNA and RNA viruses (Revankar et al. J. Med. Chem. 1984, 27, 1389-1396). Certain 7- and 9-deazaguanine C-nucleosides exhibit the ability to protect mice against a lethal challenge of Semliki Forest virus (Girgis et al. J. Med. Chem. 1990, 33, 2750-2755). Certain 6-sulfenamide and 6-sulfinamide purine nucleosides have demonstrated significant antitumor activity (Robins et al. U.S. Pat. No. 4,328,336). Certain pyrimido[5,4-D]pyrimidine nucleosides were effective in treatment against L1210 in BDF1 mice (Robins et al. U.S. Pat. No. 5,041,542), and there, the antiviral and antitumor activities of the above mentioned nucleosides were suggested to be the results of the their role as immunomdulators (Bonnet et al. J med. Chem. 1993, 36, 635-653).
One possible target of immunomodulation involves stimulation or suppression of Th1 and Th2 lymphokines. Type I (Th1) cells produce interleukin 2 (IL-2), tumor necrosis factor (TNF∀) and interferon gamma (IFN( ) and they are responsible primarily for cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. Type 2 (Th2) cells produce interleukins, IL4, IL-5, IL-6, IL-9, IL-10 and IL-13 and are primarily involved in assisting humoral immune responses such as those seen in response to allergens, e.g. IgE and IgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol, 7:145-173). D-guanosine analogs have been shown to elicit various effects on lymphokines IL-1, IL-6, IFN∀ and TNF∀ (indirectly) in vitro (Goodman, 1988, Int J Immunopharmacol, 10, 579-88) and in vivo (Smee et al., 1991, Antiviral Res 15: 229). However, the ability of the D-guanosine analogs such as 7- thio-8-oxoguanosine to modulate Type I or Type 2 cytokines directly in T cells was ineffective or had not been described.
Thus, there remains a need for novel L-nucleoside analogs, including novel purine L-nucleoside analogs. There is a particular need for novel purine L-nucleosides which have immunomodulatory activity, and especially for novel purine L-nucleosides which modulate Th1 and Th2 activity.
The present invention is directed to novel purine L-nucleoside compounds, their therapeutic uses and synthesis.
In one aspect of the invention, there are provided purine L-nucleoside, analogs of Formula I. 
wherein R1, R2, R3, R4, R5, R2xe2x80x2 and R3xe2x80x2 are independently selected from the group consisting of
H, OH, NH2, F, Cl, Br, I, N3, xe2x80x94CN, xe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x22, xe2x80x94SRxe2x80x2, xe2x80x94NHNH2, xe2x80x94NHOH, CHO, COORxe2x80x2, CONRxe2x80x22, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, I, N3, xe2x80x94CN, xe2x80x94ORxe2x80x3, NO2, xe2x80x94NRxe2x80x32, SRxe2x80x3, xe2x80x94NHNH2, xe2x80x94NHOH, COORxe2x80x3, CONRxe2x80x32 and where Rxe2x80x2 and Rxe2x80x3 are H, alkyl, alkenyl, alkynyl, aryl, aralkyl;
W=O, S, CH2, Se;
Z1, Z2 are independently selected from N, C, CH;
Z3, Z4, Z5, are independently selected from the group consisting of xe2x80x94CRxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sexe2x80x94, xe2x80x94Cxe2x95x90O, xe2x80x94Cxe2x95x90S, xe2x80x94Sxe2x95x90O, xe2x80x94CRxe2x95x90CRxe2x80x94, xe2x80x94CRxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, where R is selected from the group consisting of H, F, Cl, Br, I, N3, xe2x80x94CN, xe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x22, xe2x80x94SRxe2x80x2, xe2x80x94NHNH2, xe2x80x94NHOH, xe2x80x94NO2, CHO, COORxe2x80x2, CONH2, xe2x80x94C(O)xe2x80x94NH2, xe2x80x94C(S)xe2x80x94NH2, xe2x80x94C(NH)xe2x80x94NH2, xe2x80x94C(NOH)xe2x80x94NH2, xe2x95x90O, xe2x95x90NH, xe2x95x90NOH, xe2x95x90NR, alkyl, alkenyl, aralkyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from H, xe2x80x94OH, NH2, F, Cl, Br, I, N3, xe2x80x94CN, xe2x80x94COORxe2x80x3, xe2x80x94CONRxe2x80x32, xe2x80x94ORxe2x80x3, xe2x80x94NRxe2x80x32, xe2x80x94SRxe2x80x3, xe2x80x94NHNH2, xe2x80x94NHOH, xe2x80x94NO2, and Rxe2x80x2, Rxe2x80x3 are H, alkyl, alkenyl, alkynyl, aryl, aralkyl, acetyl, acyl, sulfonyl;
The Chemical bond between Z3 and Z4 or Z4, and Z5 is selected from Cxe2x80x94C, Cxe2x95x90C, Cxe2x80x94N, Cxe2x95x90N, Nxe2x80x94N, Nxe2x95x90N, Cxe2x80x94S, Nxe2x80x94S;
X and Y are independently selected from the group consisting of H, OH, NH2, F, Cl, Br, I, N3, xe2x80x94Sxe2x80x94NH2, xe2x80x94S(O)xe2x80x94NH2, xe2x80x94S(O2)xe2x80x94NH2, xe2x80x94CN, xe2x80x94COORxe2x80x2, xe2x80x94CONRxe2x80x22, xe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x22, xe2x80x94SRxe2x80x2, xe2x80x94NHNH2, xe2x80x94NHOH, alkyl, alkenyl, alkylnyl, aryl, aralkyl, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted aryl, substituted aralkyl, where the substituent is selected from F, Cl, Br, I, N3, xe2x80x94CN, xe2x80x94ORxe2x80x3, NO2, xe2x80x94NRxe2x80x32, SRxe2x80x3, xe2x80x94NHNH2, xe2x80x94NHOH, and Rxe2x80x2, Rxe2x80x3 are H, alkyl, alkenyl, alkynyl, aryl, aralkyl;
with the proviso that where W is O, and where R1 and R4 are H, and where R2, R3, and R5 are OH, then Z1, Z2, and Z5 are not N, Z3 is not S, Z4 is not CO, Y is not NH2, and X is not OH;
In another aspect of the invention, a pharmnaceutical composition comprises a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable ester or salt thereof admixed with at least one pharnacutically acceptable carrier.
In yet another aspect of the invention a compound according to Formulas I is used in the treatment of any condition which responds positively to administration of the compound, and according to any formulation and protocol which achieves the positive response. Among other things it is contemplated that compounds of Formula I may be used to treat an infection, an infestation, a cancer, tumor or other neoplasm, or an autoimmune disease.